In previous work it was found that inorganic pyrophosphate (PP sub i) inhibits both formation and dissolution of hydroxyapatite crystals in vitro. PP sub i, which has long been known to be present in bone, has further been detected in teeth, saliva, urine and blood. In the latter, elevated levels of PP sub i, were found in three diseases of failure of calcification, i.e. hypophosphatasia, osteomalacia and renal failure. Thus it is possible that this compound could have a physiological role in the process of calcification. Compounds related to PP sub i, but containing a P-C-P bond instead of a P-O-P bond, have been found to have similar effects in vitro. These substances, called diphosphonates, are not broken down in the body. When administered to animals and man, they inhibit both ectopic calcification induced by various means and bone resorption. Certain diphosphonates also inhibit bone mineralization. It is now planned to investigate: 1. The influence of PP sub i and diphosphonates in an in vitro calcification system involving matrix vesicles. 2. The handling of PP sub i by bone. 3. The handling of diphosphonates by cells. 4. The renal handling of diphosphonates. 5. The cellular effect of diphosphonates. 6. The use of diphosphonates to study calcium and vitamin D metabolism.